Submissions for variant NM_000053.4(ATP7B):c.3796G>A (p.Gly1266Arg)

gnomAD frequency: 0.00006  dbSNP: rs121907992

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000004053	SCV000192351	pathogenic	Wilson disease	2013-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004053	SCV000694454	pathogenic	Wilson disease	2017-04-20	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.3796G>A (p.Gly1266Arg) variant involves the alteration of a highly conserved nucleotide. The variant is located within the putative ATP binding site of the conserved P-type ATPase Cu-like domain and 5/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by the functional study, Huster_2012, where G1266R was shown to markedly affect copper transport and abolish catalytic phosphorylation. This variant was found in 6/120738 control chromosomes at a frequency of 0.000049, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant was identified in multiple affected individuals in compound heterozygosity with clinically and biochemically confirmed Wilsons disease (WD). The codon Gly1266 appears to be a mutational hot-spot, as other alteration, such as p.G1266E, p.G1266W and p.G1266V, have been reported in patients with WD. Taken together, this variant is classified as Pathogenic.
Counsyl	RCV000004053	SCV000790258	pathogenic	Wilson disease	2017-03-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004053	SCV001205969	pathogenic	Wilson disease	2024-08-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1266 of the ATP7B protein (p.Gly1266Arg). This variant is present in population databases (rs121907992, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 7626145, 11243728, 21610751). ClinVar contains an entry for this variant (Variation ID: 3849). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000004053	SCV001448794	likely pathogenic	Wilson disease	2018-05-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001507825	SCV001713634	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	PP1, PP3, PP4, PM2_moderate, PS3, PS4_moderate
GeneDx	RCV001507825	SCV001788453	pathogenic	not provided	2021-03-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate damaging effects, including low copper uptake and inactive catalytic phosphorylation (Huster et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21610751, 11243728, 7626145, 10502777, 22692182, 22240481, 24253677, 23518715)
Genome-Nilou Lab	RCV000004053	SCV001977233	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000004053	SCV002506297	pathogenic	Wilson disease	2023-09-21	criteria provided, single submitter	clinical testing	The ATP7B c.3796G>A; p.Gly1266Arg variant (rs121907992) is reported in the literature in several individuals affected with Wilson disease (Butler 2001, Moller 2011, Thomas 1995). This variant is also reported in ClinVar (Variation ID: 3849), and is found in the general population with an overall allele frequency of 0.0036% (10/280988 alleles) in the Genome Aggregation Database. The glycine at codon 1266 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.968). In vitro functional analyses demonstrate a loss of protein function (Huster 2012). Additionally, other amino acid substitutions at this codon (Glu, Trp, Val) have been reported in individuals with Wilson disease and are considered pathogenic (Li 2013, Pena-Quintana 2012, Shah 1997). Based on available information, this variant is considered to be pathogenic. References: Butler P et al. Molecular diagnosis of Wilson disease. Mol Genet Metab. 2001 Mar;72(3):223-30. PMID: 11243728. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. PMID: 22240481. Li K et al. Mutational analysis of ATP7B in north Chinese patients with Wilson disease. J Hum Genet. 2013 Feb;58(2):67-72. PMID: 23235335. Moller LB et al. Clinical presentation and mutations in Danish patients with Wilson disease. Eur J Hum Genet. 2011 Sep;19(9):935-41. PMID: 21610751. Pena-Quintana L et al. Manifestations and evolution of Wilson disease in pediatric patients carrying ATP7B mutation L708P. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):48-54. PMID: 21832955. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. PMID: 9311736. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. PMID: 7626145.
Fulgent Genetics, Fulgent Genetics	RCV000004053	SCV002809807	pathogenic	Wilson disease	2024-02-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004053	SCV004216312	pathogenic	Wilson disease	2024-03-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001507825	SCV004704322	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATP7B: PM3:Strong, PS1, PM1, PM2, PM5, PP3, PP4, PS3:Supporting
All of Us Research Program, National Institutes of Health	RCV000004053	SCV004829448	pathogenic	Wilson disease	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1266 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts copper uptake and transport (PMID: 22240481, 22692182). This variant has been reported in individuals affected with Wilson disease (PMID: 10502777, 11243728, 21610751, 23518715, 36096368). In some of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene, while heterozygous carriers of this variant were determined to be unaffected. These data indicate that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 10/280988 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004053	SCV004847798	pathogenic	Wilson disease	2020-06-11	criteria provided, single submitter	clinical testing	The p.Gly1266Arg variant in ATP7B has been previously reported in >20 patients with Wilson disease, including at least 8 compound heterozygotes and 1 homozygote, and segregated in an affected relative (Butler 2001, Coffey 2013, Curtis 1999, Moller 2011, Thomas 1995). This variant has also been reported in ClinVar (Variation ID 3849) and is present in 0.01% (3/24200) of African and 0.005% (7/128724) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analysis suggest an impact to the protein. Furthermore, an in vitro study suggested an impact on protein function (Huster 2012). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP1, PP3, PP4, PS3_Supporting.
OMIM	RCV000004053	SCV000024219	pathogenic	Wilson disease	1995-02-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000004053	SCV001455582	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001507825	SCV001927289	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001507825	SCV001956112	pathogenic	not provided		no assertion criteria provided	clinical testing